Angiotensin II treatment is associated with improved oxygenation in ARDS patients with refractory vasodilatory shock

Background The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS. Methods Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO2/FiO2-ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality. Results Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg [95%CI 35.2–161.5], p = 0.0028). Similarly, oxygenation index decreased by − 6.0 cmH2O/mmHg at hour-48 with angiotensin-II versus − 0.4 cmH2O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH2O/mmHg, [95%CI − 8.6 to − 1.1], p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% [95%CI 6.5–47.0%], p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group. Conclusions In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock. Trial Registration: ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015). Supplementary Information The online version contains supplementary material available at 10.1186/s13613-023-01227-5.


Missing Data Management
For the primary analysis of respiratory measures at hour-48, we used complete-case analysis.This method was selected instead of multiple imputation because imputation assumes data to be missing at random and can be more prone to producing biased estimates when this assumption is violated. 1 this study, all patients with missing hour-48 P:F were missing this data because they died prior to that timepoint, and therefore the data were not randomly missing.We took several steps to ensure analysis were not distorted by subject attrition.First, the mixed-effects models used in the vasopressor dose analysis provide a validity check, as these models are robust to attrition bias. 2 Next, we performed two additional sensitivity analyses under optimistic and pessimistic assumptions.
For the first of these, we re-performed the primary analysis using last-observation carried forward (LOCF) for the patients that died before hour-48.LOCF likely assigns optimistic values because it may attribute a less severely abnormal value to a patient that subsequently had a poor outcome.The pessimistic sensitivity analysis used worst-case values, where patients that died before outcome measurement were assigned an extreme value for the hour-48 time point.These were P:F=50, PaO2=50, FiO2 = 100%, OI = 50, and VR = 4.0, respectively.This approach may attribute overly pessimistic values to patients that may have had less severe respiratory dysfunction had they survived to hour-48.
We reasoned that while all four approachesi.e., complete-case, mixed-effects models, LOCF, and worst-case valuesall have potential advantages and disadvantages, concordant results between them would suggest that attrition bias was unlikely to be affected our study's results.

Additional Sensitivity and Subgroup Analyses
As additional sensitivity analyses to account for prior ACE-inhibitor or ARB exposure, we recapitulated both when excluding these patients as well as by adding a covariate the multivariable model for ACE-inhibitor/ARB exposure.We similarly performed sensitivity analysis excluding patients that received extracorporeal membrane oxygenation.Finally, as a post-hoc exploratory analysis, we assessed whether the effect of angiotensin-II on the primary outcome of hour-48 P:F varied by baseline hypoxemia severity.We first recapitulated the primary analysis, stratifying patients based on whether baseline hypoxemia was mild (P:F 200-299), moderate (P:F 100-199), or severe (P:F <100).
We next analyzed the baseline P:F continuously by including an interaction term for baseline P:   Displays the mean fluid volumes and differences between groups in administered fluid volumes during the study drug titration period.The 95% confidence interval and p-value were calculated using an unpaired T-test with Welch's correction for unequal variances.Abbreviations: ∆difference; SDstandard deviation; P:F -PaO2/FiO2 Ratio; ARBangiotensin receptor blocker; ACEangiotensin converting enzyme; 95%CI -95% confidence interval.Abbreviations: ∆difference; SDstandard deviation; ECMO -extracorporeal mechanical oxygenation; 95%CI -95% confidence interval.

Figure S1 :
Figure S1: Directed Acyclic Graph for Direct vs. Indirect Effect of Angiotensin-II

Figure S2 :
Figure S2: Duration of Study Drug Exposure Respiratory physiologic measures at hour-48 in angiotensin-II vs. placebo under different missing data management strategies.The Hour-48 columns show the average measures within the treatment group.The ∆ vs. hour-0 columns show the mean difference at Hour-48 vs. baseline within the treatment group, displayed as: Hour-48 -Hour-0.The baseline-adjusted ∆ column reflects the estimate for difference in means by for angiotensin-II vs. placebo groups from the linear model adjusted for the hour-0 value (primary analysis).Abbreviations: ∆difference; SDstandard deviation; P:F -PaO2/FiO2 Ratio; PaO2arterial partial pressure of oxygen; FiO2fraction of inspired oxygen; mAwPmean airway pressure; PEEPpositive end-expiratory pressure; PaCO2arterial partial pressure of carbon dioxide.
Displays P:F at hour-48 in angiotensin-II vs. placebo when excluding the n=4 patients with exposure to ECMO during the trial period.The Hour-48 columns show the average P:F within the treatment group.The ∆ vs. hour-0 columns show the mean difference at Hour-48 vs. baseline within the treatment group, displayed as: Hour-48 -Hour-0.The 95% CI and p-values in these columns reflect the results of a paired T-test.The baseline-adjusted ∆ column reflects the estimate for difference in means by for Angiotensin-II vs. Placebo groups from the linear model adjusted for the hour-0 value (primary analysis).

Table S3 : Full Multivariable Model for PaO2/FiO2 Ratio at Hour 48
Full output for the multivariable fixed-effects model for P:F Ratio at hour-48.Effect estimate refers to the change in P:F Ratio associated with a 1-unit increase in the indicated continuous variable or vs. the reference group for binary variables.Abbreviations: P:F Ratio -PaO2/FiO2 Ratio; MAPmean arterial pressure; NEDnorepinephrine equivalent dose; APACHE-IIacute physiology and chronic health II score; PEEPpositive endexpiratory pressure.

Table S4 : Full Multivariable Model for Oxygenation Index at Hour 48
Full output for the multivariable fixed-effects model for oxygenation index at hour-48.Effect estimate refers to the change in P:F Ratio associated with a 1-unit increase in the indicated continuous variable or vs. the reference group for binary variables.

Table S5 : Full Multivariable Model for Ventilatory Ratio at Hour 48
Full output for the multivariable fixed-effects model for ventilatory ratio at hour-48.Effect estimate refers to the change in P:F Ratio associated with a 1-unit increase in the indicated continuous variable or vs. the reference group for binary variables.Abbreviations: MAPmean arterial pressure; NEDnorepinephrine equivalent dose; APACHE-IIacute physiology and chronic health II score; PEEPpositive end-expiratory pressure.

Table S7 : Sensitivity Analyses For PaO2/FiO2 Ratio at Hour-48 Excluding Patients With Prior Exposure to ARBs or ACE-Inhibitors (All Missing Data Approaches)
Displays P:F at hour-48 in angiotensin-II vs. placebo when excluding patients with prior exposure to ARBs or ACE-inhibitors under all missing data management strategies.The Hour-48 columns show the average P:F within the treatment group.The ∆ vs. hour-0 columns show the mean difference at Hour-48 vs. baseline within the treatment group, displayed as: Hour-48 -Hour-0.The 95% CI and p-values in these columns reflect the results of a paired T-test.The baseline-adjusted ∆ column reflects the estimate for difference in means by for Angiotensin-II vs. Placebo groups from the linear model adjusted for the hour-0 value (primary analysis).

Table S8 : Sensitivity Analysis -Full Multivariable Model for PaO2/FiO2 Ratio at Hour 48 Including Adjustment for Prior ARB and ACE-Inhibitor Exposure
Full output for the sensitivity analysis multivariable fixed-effects model for P:F Ratio at hour-48 that also adjusted for prior ARB/ACEi exposure.Effect estimate refers to the change in P:F Ratio associated with a 1-unit increase in the indicated continuous variable unless otherwise indicated or the change vs. the reference group for binary variables.Abbreviations: P:F Ratio -PaO2/FiO2 Ratio; MAPmean arterial pressure; NEDnorepinephrine equivalent dose; APACHE-IIacute physiology and chronic health II score; PEEPpositive end-expiratory pressure; ARBangiotensin receptor blocker; ACEi -Angiotensin Converting Enzyme Inhibitor; 95%CI -95% confidence interval.